Recommendations for the design of small population clinical trials

Background Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases. Results The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients’ engagement in study design. Conclusions Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy’s safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered

RF-Separated Beam Project for the M2 Beam Line at CERN

Within the framework of the Physics Beyond Colliders initiative at CERN, discussions are underway on the feasibility of producing radio-frequency (RF) separated beams for Phase-2 of the AMBER experiment at the M2 beam line in the North experimental area of the CERN SPS. The technique of RF separation is applied to enrich the content of a certain particle type within a beam consisting of different species at the same momentum. It relies on the fact that each particle type has a different velocity, decreasing with rest mass. The successor of the COMPASS experiment, AMBER, requires for its Phase-2 measurements high-intensity, high-purity kaon (and antiproton) beams, which cannot be delivered with the currently existing conventional M2 beam line. The present contribution introduces the principle of RF separation and explains its dependence on different parameters of beam optics and hardware. The first examination of potential showstoppers for the RF-separated beam implementation is presented, based on the particle production rates, beam line transmission for specific optics settings, limitations for overall beam intensity and purity posed by beam line acceptance and radiation protection. Different beam optics settings have been examined, providing either focused or parallel beams inside the RF cavities. The separation and transmission capability of the different optics settings for realistic characteristics of RF cavities are discussed and the preliminary results of the potential purity and intensity of the RF-separated beam are presented. They illustrate the high importance of an RF-separated kaon beam for many of the AMBER Phase-2 data taking programs, such as spectroscopy, prompt-photon production, Primakoff reactions and kaon charge-radius measurement

ARIA 2016 : Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.Peer reviewe

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Augustins Tropus-Begriff: Umfang und Struktur. Beitrag zu einer tropologischen Hermeneutik. Wiener Studien|Wiener Studien 124 124|

This paper explores the concept ‘trope’ in the text of Augustine. After preliminary remarks on tropus, first, I analyse Augustine’s theory of sign in the second part of De magistro where Augustine defines the sign as a unit consisting of the signifier and the signified and illustrates the pragmatic conditions under which a signifier is interpreted as a sign. Second, I point out that according to the pragmatic dimension of Augustine’s biblical hermeneutics the reference of the biblical texts to the regula fidei is essential to the distinction between the literal and the figurative or tropical meaning and consequently to the extension of ‘trope’ which Augustine describes as meaning one thing in saying another. Third, I explain the tradition, the logical principles, and the classification of the tropes which are found in Augustine. Finally, the paper sheds light on the importance of the knowledge of trope to the biblical exegesis

Beobachtungen und Experimente uber die Entstehung der Bienenwabe (Apis mellifica L).

Diss. Berlin.OPLADEN-RUG0